Perugia: Etruscan Arch
Perugia: Town Hall and Fountain
Perugia: University Medical Center
Visit of Dr. James Smith and his wife to our medical center.
HAIRY CELL LEUKEMIA AS A PARADIGM FOR DEVELOPMENT OF NEW THERAPIES
1958(Blood)
Recognition as clinico-pathological entity
Splenectomy
1984 (NEJM)
Interferon
1990(NEJM)
Pentostatin Cladribin
2011(NEJM)
Mutated BRAF (targeted therapy ?)
Any place for molecular targeted therapy of HCL with BRAF-V600E inhibitors ?
- About 40% of HCL patients treated with purine analogs (cladribin or pentostatin) will relapse within 5-10 years. Major problem especially for younger patients.
- Myelotoxicity after multiple course of chemotherapy
- Severe immune depression after purine analogues (increased risk of opportunistic infections
RAS
RTK
V600E
MEK
ERK
BRAF
SurvivalProliferation
Transformation
VEMURAFENIB DABRAFENIB
BRAF mutation causes constitutive activation of MAPK pathwaysustaining survival of hairy cells: is it druggable ?
Increased phosphorylation
(Flaherty et al., NEJM 2010)
Clinical activity of the Vemurafenib in metastatic melanoma with BRAF V600E
Vemurafenib (PLX4032)
- First BRAF-V600E inhibitor
- Orally available compound
- Dosage (960 mg, twice daily)
- Clinical activity in metastatic melanoma
- FDA approved for this indication (2011)
Effect of Vemurafenib on HCL cells
Cell death
Hairy cell
Drug
Trimming ofhairy cells
HCL-PG01 CLINICAL TRIALSponsor: Institute of Hematology, Perugia (PI: B. Falini)
Vemurafenib (Zelboraf – Roche):
N= 28 patients with refractory orrelapsed HCL have been recruited
Vemurafenib 960 mg twice/day
(8 weeks)
CR
Stop therapy X 2 weeks
Stop drug
Vemurafenib 960 mg twice/day
(4 weeks)
no CRCR
no CR
Vemurafenib 960 mg twice/day
(4 weeks)
Stop drug
Stop drug
CR= Defined according to standard criteria